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Free Radic Biol Med. 2012 Feb 1;52(3):671-682. doi: 10.1016/j.freeradbiomed.2011.11.012. Epub 2011 Dec 1.

Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling.

Author information

1
Department of Internal Medicine and Department of Biochemistry and Cell Biology, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea.
2
Department of Internal Medicine and Department of Biochemistry and Cell Biology, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122, USA.
3
Department of Internal Medicine and Department of Biochemistry and Cell Biology, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea. Electronic address: jongikim@hotmail.com.
4
Department of Internal Medicine and Department of Biochemistry and Cell Biology, Research Institute of Aging and Metabolism, WCU Program, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea. Electronic address: leei@knu.ac.kr.

Abstract

Sulforaphane (SFN) is a dietary isothiocyanate that exerts chemopreventive effects via NF-E2-related factor 2 (Nrf2)-mediated induction of antioxidant/phase II enzymes, such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). This work was undertaken to evaluate the effects of SFN on hepatic fibrosis and profibrotic transforming growth factor (TGF)-β/Smad signaling, which are closely associated with oxidative stress. SFN suppressed TGF-β-enhanced expression of α-smooth muscle actin (α-SMA), a marker of hepatic stellate cell (HSC) activation, and profibrogenic genes such as type I collagen, fibronectin, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and plasminogen activator inhibitor (PAI)-1 in hTERT, an immortalized human HSC line. SFN inhibited TGF-β-stimulated activity of a PAI-1 promoter construct and (CAGA)(9) MLP-Luc, an artificial Smad3/4-specific reporter, in addition to reducing phosphorylation and nuclear translocation of Smad3. Nrf2 overexpression was sufficient to inhibit the TGF-β/Smad signaling and PAI-1 expression. Conversely, knockdown of Nrf2, but not inhibition of HO-1 or NQO1 activity, significantly abolished the inhibitory effect of SFN on (CAGA)(9) MLP-Luc activity. However, inhibition of NQO1 activity reversed repression of TGF-β-stimulated expression of type I collagen by SFN, suggesting the involvement of antioxidant activity of SFN in the suppression of Smad-independent fibrogenic gene expression. Finally, SFN treatment attenuated the development and progression of early stage hepatic fibrosis induced by bile duct ligation in mice, accompanied by reduced expression of type I collagen and α-SMA. Collectively, these results show that SFN elicits an antifibrotic effect on hepatic fibrosis through Nrf2-mediated inhibition of the TGF-β/Smad signaling and subsequent suppression of HSC activation and fibrogenic gene expression.

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